© Elsevier, 2011.Principles of Molecular Virology Virus Pathogenesis How virus infection may injure the body How HIV infection causes AIDS How some viruses

Principles of Molecular Virology © Elsevier, 2011.

Virus PathogenesisVirus Pathogenesis

• How virus infection may injure the body

• How HIV infection causes AIDS

• How some viruses cause cancer

• Emergent viruses


Mechanisms of Cellular InjuryMechanisms of Cellular Injury

• Altered shape

• Detachment from the substrate

• Lysis

• Membrane fusion

• Membrane permeability

• Inclusion bodies

• Apoptosis


Viruses and Immunodeficiency - Viruses and Immunodeficiency - HIV and AIDSHIV and AIDS


HIV and AIDSHIV and AIDS

• HIV infects CD4+ cells

• CD4 + cells are constantly being eliminated by HIV

infection while the body is constantly replacing them

• Over time, CD4 counts drop, leaving the body

susceptible to the infections that define AIDS

• Antigenic variation is important in the biology of HIV


Virus-Related Diseases - SSPEVirus-Related Diseases - SSPE

Measles - subacute sclerosing panencephalitis (SSPE)

(about 1 in 300,000 cases):

– Virus replication continues at a low level, but

defects in the envelope protein genes prevent the

production of extracellular infectious virus particles

– Lack of envelope protein production causes failure

of the immune system to recognize and eliminate

infected cells


Virus-Related Diseases - DengueVirus-Related Diseases - Dengue


Bacteriophages and Human Bacteriophages and Human DiseaseDisease

• Stx1 and Stx2 toxin genes are encoded by lysogenic

prophages in Escherichia coli

Other bacterial virulence determinants are also encoded

by lysogenic phages:

• Diphtheria toxin

• Streptococcus erythrogenic toxins

• Staphylococcus enterotoxins


Cell Transformation by VirusesCell Transformation by Viruses

Transformed cells have an altered phenotype:

• Loss of anchorage dependence

• Loss of contact inhibition

• Colony formation in semi-solid media

• Decreased requirements for growth factors


Cell Transformation by VirusesCell Transformation by Viruses

Transformation is mediated by proteins encoded by

oncogenes:

• Oncogenes and proto-oncogenes

• Tumour suppressor genes

• DNA repair genes


OncogenesOncogenes


OncogenesOncogenes


Cell Transformation by Cell Transformation by RetrovirusesRetroviruses

Not all retroviruses are capable of transforming cells (e.g. HIV)

• Transduction• Cis-activation• Trans-activation


Cell Transformation by DNA Cell Transformation by DNA VirusesViruses

• Several families of DNA viruses are capable of

transforming cells

• Interact with cellular proteins which have a negative

regulatory role in cell proliferation - p53 and pRb


SV40 T-antigenSV40 T-antigen

Binds to p53, allows DNA replication


DNA Transforming VirusesDNA Transforming Viruses

• Adenoviruses

• Human papillomavirus (HPV)


Viruses and CancerViruses and Cancer

• Epstein Barr Virus (EBV)

• Hepatitis B Virus (HBV)

• Hepatitis C Virus (HCV)

• Human Herpesvirus 8 (HHV-8)

• Human Papillomaviruses (HPV)

• Human T-Cell Leukaemia Virus (HTLV)


New and Emergent VirusesNew and Emergent Viruses

• Poliovirus - changed with time?

• Measles virus

• Smallpox virus


ArbovirusesArboviruses

• Yellow fever virus• Hantaviruses• West Nile virus• Chikungunya virus


ZoonosesZoonoses

• Many emergent virus diseases are zoonoses

(transmitted from animals to humans)

• Ebola virus (1976)

• Severe acute respiratory syndrome (SARS) (2003)


Bioterrorism?Bioterrorism?

• Smallpox

• Haemorrhagic fevers - filoviruses and arenaviruses


SummarySummary

• Virus pathogenesis is complex, variable, relatively

rare• Pathogenesis is determined by the balance between

host and virus factors• The immune system also plays a part in causing

symptoms and damage• Some viruses can transform cells so that they

continue to grow indefinitely• Approximate 20% of human cancers are thought to be

due to viruses


Further ReadingFurther Reading

Best, S.M. (2008) Viral Subversion of Apoptotic Enzymes: Escape from Death Row. Annual Review of Microbiology 62: 171-192

Casadevall, A. and Pirofski, L.A. (2004) The weapon potential of a microbe. Trends in Microbiology, 12: 259–263

Coiras M., López-Huertas M.R., Pérez-Olmeda, M. and Alcamí, J. (2009) Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs. Nature Reviews Microbiol. 7(11): 798-812

DeCaprio, J.A. (2009) How the Rb tumor suppressor structure and function was revealed by the study of Adenovirus and SV40. Virology 384(2): 274-284

Donlan, R.M. (2009) Preventing biofilms of clinically relevant organisms using bacteriophage. Trends in Microbiol. 17(2): 66-72

Douek, D.C. et al. (2003) T cell dynamics in HIV-1 infection. Annual Review of Immunology, 21: 265–304

Forsman, A. and Weiss R.A. (2008) Why is HIV a pathogen? Trends Microbiol. 16(12): 555-560

Hay, S. and Kannourakis, G. (2002) A time to kill: viral manipulation of the cell death program. J Gen Virol. 83: 1547-1564

Jansen, K.U. and Shaw, A.R. (2004) Human papillomavirus vaccines and prevention of cervical cancer. Annual Review of Medicine, 55: 319–331

Kyle, J.L. and Harris E. (2008) Global spread and persistence of dengue. Ann Rev Microbiol. 62: 71-92

LaBeaud, A.D., Kazura, J.W. and King, CH. (2010) Advances in Rift Valley fever research: insights for disease prevention. Curr Opin Infect Dis. 23(5): 403-408

Racaniello, V.R. (2006) One hundred years of poliovirus pathogenesis. Virology. 344(1): 9-16

Randolph, S.E. and Rogers, DJ. (2010) The arrival, establishment and spread of exotic diseases: patterns and predictions. Nat Rev Microbiol. 8(5): 361-371

Sierra, S., Kupfer, B. and Kaiser, R. (2005) Basics of the virology of HIV-1 and its replication. J Clin Virol. 34(4): 233-244

Stephen, A., Mims, C.A. and Nash, A. (2000) Mims’ Pathogenesis of Infectious Disease, 5th ed. Academic Press, London. ISBN 0124982654

Thorley-Lawson, D.A. and Allday, M.J. (2008) The curious case of the tumour virus: 50 years of Burkitt's lymphoma. Nature Rev Microbiol. 6(12): 913-924

Weaver, S.C and Reisen, W.K. (2010) Present and future arboviral threats. Antiviral Res. 85(2): 328-345.

Weiss, R.A. (2002) Virulence and pathogenesis. Trends in Microbiology, 10: 314–317

Whitehead, S.S., Blaney, J.E., Durbin, A.P. and Murphy, B.R. (2007) Prospects for a dengue virus vaccine. Nature Rev Microbiol. 5(7): 518-528

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© Elsevier, 2011.Principles of Molecular Virology Virus Pathogenesis How virus infection may injure the body How HIV infection causes AIDS How some viruses